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GENE EXPRESSION DOSE-RESPONSE IN THE MOUSE BLADDER FOLLOWING EXPOSURE TO ARSENATE IN DRINKING WATER
Citation:
CLEWELL, H. J., R. S. THOMAS, E. M. KENYON, M. F. HUGHES, AND J. YAGER. GENE EXPRESSION DOSE-RESPONSE IN THE MOUSE BLADDER FOLLOWING EXPOSURE TO ARSENATE IN DRINKING WATER . Presented at Society of Toxicology Annual Meeting, Charlotte, NC, March 25 - 29, 2007.
Description:
The association between drinking water exposures to inorganic arsenic and life-threatening tumors in the human is strongest for bladder cancer. Moreover, a working model for the pathogenesis of human bladder cancer has been developed. To investigate the mode of action for inorganic arsenic carcinogenicity in the bladder, a study was conducted to explore the dose-response for genomic expression in bladder epithelial cells resulting from exposure of C53Bl/6J mice to arsenate in drinking water for up to 12 weeks at concentrations ranging from 0.05 to 50 mg As/L. Bladder and urine concentrations of all arsenic species, including arsenite and the methylated metabolites, were also determined in order to support the design of in vitro analyses on primary bladder epithelial cells at concentrations of arsenite equivalent to those achieved in the in vivo study. Animals exposed at 0.05 mg/L arsenate showed no significant differences from controls in urinary arsenic species, tissue concentrations, or bladder gene expression. However, tissue concentrations were significantly increased at the higher exposures, with MMA as the dominant species in kidney tissue and DMA in bladder and urine. In addition, a dose-dependent up-regulation in a variety of genes related to DNA repair, cell cycle control, proteotoxicity, and apoptosis was observed. This presentation will discuss the implications of these genomic data for understanding the mode of action of arsenic bladder carcinogenicity and will also describe how similar data obtained in primary human bladder epithelial cells will be used to inform the quantitative dose-response assessment for the bladder carcinogenicity of inorganic arsenic.